LEA CAMPOS DE OLIVEIRA
Projetos de Pesquisa
Unidades Organizacionais
LIM/46 - Laboratório de Parasitologia Médica, Hospital das Clínicas, Faculdade de Medicina
LIM/03 - Laboratório de Medicina Laboratorial, Hospital das Clínicas, Faculdade de Medicina
LIM/03 - Laboratório de Medicina Laboratorial, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Whole exome sequencing of Chagas disease cardiomyopathy families reveals accumulation of rare variants in mitochondrial and inflammation-associated genes(2019) CUNHA-NETO, E.; MARQUET, S.; FRADE, A. Farage; FERREIRA, A. Mota; OUARHACHE, M.; IANNI, B.; FERREIRA, L. Rodrigues Pinto; RIGAUD, V. Oliveira-Carvalho; ALMEIDA, R. Ribeiro; CANDIDO, D.; TORRES, M.; GALLARDO, F.; FERNANDES, R.; MADY, C.; BUCK, P.; CARDOSO, C.; SANTOS-JUNIOR, O. R.; OLIVEIRA, L. C.; OLIVEIRA, C. D. L.; NUNES, M. do Carmo; ABEL, L.; KALIL, J.; RIBEIRO, A. L. P.; SABINO, E. C.; CHEVILLARD, C.conferenceObject CIRCULATING MIRNAS PROFILE AS POTENTIAL SIGNATURE OF BENZNIDAZOLE TREATMENT TOXICITY IN CHAGAS PATIENTS(2017) CANDIDO, Darlan da Silva; CUNHA-NETO, Edecio; RIGAUD, Vagner O.; OLIVEIRA, Lea C. de; MOREIRA, Carlos Henrique V.; JUNIOR, Nelson G.; SOUZA, Marcela de; SABINO, Ester C.; FERREIRA, Ludmila R.- A refined genome phage display methodology delineates the human antibody response in patients with Chagas disease(2021) TEIXEIRA, Andre Azevedo Reis; CARNERO, Luis Rodriguez; KURAMOTO, Andreia; TANG, Fenny Hui Fen; GOMES, Carlos Hernique; PEREIRA, Natalia Bueno; OLIVEIRA, Lea Campos de; GARRINI, Regina; MONTEIRO, Jhonatas Sirino; SETUBAL, Joao Carlos; SABINO, Ester Cerdeira; PASQUALINI, Renata; COLLI, Walter; ARAP, Wadih; ALVES, Maria Julia Manso; CUNHA-NETO, Edecio; GIORDANO, Ricardo JoseLarge-scale mapping of antigens and epitopes is pivotal for developing immunotherapies but challenging, especially for eukaryotic pathogens, owing to their large genomes. Here, we developed an integrated platform for genome phage display (gPhage) to show that unbiased libraries of the eukaryotic parasite Trypanosoma cruzi enable the identification of thousands of antigens recognized by serum samples from patients with Chagas disease. Because most of these antigens are hypothetical proteins, gPhage provides evidence of their expression during infection. We built and validated a comprehensive map of Chagas disease antibody response to show howlinear and putative conformation epitopes, many rich in repetitive elements, allow the parasite to evade a buildup of neutralizing antibodies directed against protein domains that mediate infection pathogenesis. Thus, the gPhage platform is a reproducible and effective tool for rapid simultaneous identification of epitopes and antigens, not only in Chagas disease but perhaps also in globally emerging/reemerging acute pathogens.
- Galectin-3 Associated with Severe Forms and Long-term Mortality in Patients with Chagas Disease(2021) FERNANDES, Fabio; MOREIRA, Carlos Henrique Valente; OLIVEIRA, Lea Campos; SOUZA-BASQUEIRA, Marcela; IANNI, Barbara Maria; LORENZO, Claudia di; RAMIRES, Felix Jose Alvarez; NASTARI, Luciano; CUNHA-NETO, Edecio; RIBEIRO, Antonio L.; LOPES, Renato Delascio; KEATING, Sheila M.; SABINO, Ester Cerdeira; MADY, CharlesBackground: The histopathological characteristics of Chagas disease (ChD) are: presence of myocarditis, destruction of heart fibers, and myocardial fibrosis. Galectin-3 (Gal-3) is a biomarker involved in the mechanism of fibrosis and inflammation that may be useful for risk stratification of individuals with ChD. Objectives We sought to evaluate whether high Gal-3 levels are associated with severe forms of Chagas cardiomyopathy (CC) and whether they are predictive of mortality. Methods We studied anti-T. cruzi positive blood donors (BD): Non-CC-BD (187 BD without CC with normal electrocardiogram [ECG] and left ventricular ejection fraction [LVEF]); CC-Non-Dys-BD (46 BD with CC with abnormal ECG but normal LVEF); and 153 matched serum-negative controls. This cohort was composed of 97 patients with severe CC (CC-Dys). We used Kruskall-Wallis and Spearman's correlation to test hypothesis of associations, assuming a two-tailed p<0.05 as significant. Results The Gal-3 level was 12.3 ng/mL for Non-CC-BD, 12.0 ng/mL for CC-Non-Dys-BD, 13.8 ng/mL for controls, and 15.4 ng/mL for CC-Dys. LVEF<50 was associated with higher Gal-3 levels (p=0.0001). In our linear regression adjusted model, we found association between Gal-3 levels and echocardiogram parameters in T. cruzi-seropositive subjects. In CC-Dys patients, we found a significant association of higher Gal-3 levels (>= 15.3 ng/mL) and subsequent death or heart transplantation in a 5-year follow-up (Hazard ratio - HR 3.11; 95%CI 1.21-8.04; p=0.019). Conclusions In ChD patients, higher Gal-3 levels were significantly associated with severe forms of the disease and more long-term mortality, which means it may be a useful means to identify high-risk patients.
- Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease(2021) OUARHACHE, Maryem; MARQUET, Sandrine; FRADE, Amanda Farage; FERREIRA, Ariela Mota; IANNI, Barbara; ALMEIDA, Rafael Ribeiro; NUNES, Joao Paulo Silva; FERREIRA, Ludmila Rodrigues Pinto; RIGAUD, Vagner Oliveira-Carvalho; CANDIDO, Darlan; MADY, Charles; ZANIRATTO, Ricardo Costa Fernandes; BUCK, Paula; TORRES, Magali; GALLARDO, Frederic; ANDRIEUX, Pauline; BYDLOWSKY, Sergio; LEVY, Debora; ABEL, Laurent; CARDOSO, Clareci Silva; SANTOS-JUNIOR, Omar Ribeiro; OLIVEIRA, Lea Campos; OLIVEIRA, Claudia Di Lorenzo; NUNES, Maria Do Carmo; COBAT, Aurelie; KALIL, Jorge; RIBEIRO, Antonio Luiz; SABINO, Ester Cerdeira; CUNHA-NETO, Edecio; CHEVILLARD, ChristopheCardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-gamma and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy. Methods We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY. Results We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related - most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-gamma on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (Delta psi M), indicating mitochondrial dysfunction. Conclusion Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-gamma-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.
conferenceObject The predictive value of plasma Galectin-3 for cardiac impairment and mortality in patients with Chagas disease(2016) FERNANDES, F.; MOREIRA, C. H.; OLIVEIRA, L. C.; IANNI, B. M.; LORENZO, C. D.; RAMIRES, F. J. A.; NASTARI, L.; RIBEIRO, A. L. P.; CUNHA NETO, E.; SABINO, E. C.; MADY, C.- Anti-Trypanosoma cruzi antibody profiling in patients with Chagas disease treated with benznidazole assessed by genome phage display(2023) CARNERO, Luis Antonio Rodriguez; KURAMOTO, Andreia; OLIVEIRA, Lea Campos de; MONTEIRO, Jhonatas Sirino; SETUBAL, Joao Carlos; CUNHA-NETO, Edecio; SABINO, Ester Cerdeira; GIORDANO, Ricardo JoseBackgroundThere have been significant improvements in Chagas disease therapy and it is now widely accepted that most patients with chronic disease might benefit from therapy. However, there are challenges to monitor drug efficacy and cure for these patients, which are important impediments for current and future therapies. Trypanosoma cruzi-PCR is highly variable while IgG seroconversion takes decades yielding variable results depending on the antigen(s) used for the assay. Methods and resultsWe used the genomic phage display (gPhage) platform to perform a pairwise comparison of antigens and epitopes recognized by twenty individual patients with chronic Chagas disease before and after treatment with benznidazole. In total, we mapped 54,473 T. cruzi epitopes recognized by IgG from individual patients (N = 20) before benznidazole treatment. After treatment, the number of epitopes recognized by all patients was significantly smaller (21,254), a reduction consistent with a decrease in anti-T. cruzi antibodies. Most of these epitopes represent distinct fragments from the same protein and could, therefore, be grouped into 80 clusters of antigens. After three years of treatment with benznidazole, we observed a 64% reduction in the number of clusters of antigens recognized by patients (59 clusters before versus 21 clusters after treatment). The most abundant antigenic clusters recognized by patients correspond to the surface antigen CA-2 (B13) followed by the microtubule associated antigen, which highlights the value of these epitopes in Chagas disease diagnosis. Most importantly, quantitative pairwise comparison of gPhage data allowed for the prediction of patient response to treatment based on PCR status. Principal findingHere, we compiled a list of antigens and epitopes preferentially recognized by Chagas disease patients before and after benznidazole treatment. Next, we observed that gPhage data correlated with patient PCR-status and could, therefore, predict patient response to treatment. Moreover, gPhage results suggest that overall, independent of PCR status, treatment led to a reduction in the presence of T. cruzi-specific antibody levels and the number of antigens and epitopes recognized by these patients. ConclusionThe gPhage platform use of unbiased library of antigens, which is different from conventional serological assays that rely on predetermined antigens, is a contribution for the development of novel diagnostic tools for Chagas disease. Author summaryChagas disease, caused by the single-celled parasite Trypanosoma cruzi, can be a life-treating and debilitating illness. Because there is no vaccine and currently the only two available drugs are most effective if used during the early acute stage of the disease, treatment options for infected individuals are limited. Most individuals will only find out they have Chagas disease during a routine medical examination or in blood bank while donating blood, in which cases, they are already chronically infected. At this stage, treatment will not undo clinical mani-festations (i.e., cardiomyopathy) but may eliminate the parasite and prevent disease progression. Currently, polymerase chain reaction (PCR) and serological assays are the only diagnostic tools available, both with limi-tations in sensitivity and accuracy. The lack of effective molecular markers thus prevents physicians to deter-mine whether a patient is parasite free and cured from the disease. It also has important implications for the development of new drugs to treat Chagas disease. Here, we studied the reactivity of anti-T. cruzi antibodies in sera from a cohort of 20 patients that underwent treatment for Chagas disease using a new method developed by our group named gPhage. Using gPhage, we scanned all T. cruzi proteins to identify those that were reactive with the antibodies from each individual patient before and after treatment. In sum, gPhage data correlated with patient PCR-status and could, therefore, predict patient response to treatment. It also revealed a new set of T. cruzi proteins that could be useful for the development of future diagnostic methods.
- Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction (vol 215, pg 387, 2017)(2020) FERREIRA, Ludmila Rodrigues Pinto; FERREIRA, Frederico Moraes; NAKAYA, Helder Imoto; DENG, Xutao; CANDIDO, Darlan da Silva; OLIVEIRA, Lea Campos de; BILLAUD, Jean-Noel; LANTERI, Marion C.; RIGAUD, Vagner Oliveira-Carvalho; SEIELSTAD, Mark; KALIL, Jorge; FERNANDES, Fabio; RIBEIRO, Antonio Luiz Pinho; SABINO, Ester Cerdeira; CUNHA-NETO, Edecio
- Cohort profile update: the main and new findings from the SaMi-Trop Chagas cohort(2021) OLIVEIRA, Claudia Di Lorenzo; CARDOSO, Clareci Silva; BALDONI, Nayara Ragi; NATANY, Larissa; FERREIRA, Ariela Mota; OLIVEIRA, Lea Campos de; NUNES, Maria do Carmo Pereira; QUINTINO, Nayara Dornela; BIERRENBACH, Ana Luiza; BUSS, Lewis F.; HAIKAL, Desiree Sant'Ana; NETO, Edecio Cunha; RIBEIRO, Antonio Luiz Pinho; SABINO, Ester CerdeiraThe SaMi-Trop project is a cohort study conducted in 21 municipalities of endemic areas of Chagas disease, including 1,959 patients with chronic Chagas cardiomyopathy. In this article we updated the results of the project, adding information from the second cohort visit. Trypanosoma cruzi-seropositive patients were enrolled from the primary care Telehealth service in Minas Gerais State, Brazil. The eligibility criterium for the second visit was the participation in the baseline evaluation. Of 1,959 participants at the baseline assessment, 1,585 (79.9%) returned after two years for the second evaluation. The mortality rate was 6.7%, but varied from 0.9% to 18.2% when it was stratified by certain clinical characteristics. A lower age-adjusted NT-Pro-BNP level (less than 300) and a prior benznidazole treatment were associated with lower mortality. There was an improvement in most quality of life domain scores. Participants have also reported fewer signs and symptoms and greater use of medication. The second follow-up visit will be complete in Oct 2021.
- Longitudinal study of patients with chronic Chagas cardiomyopathy in Brazil (SaMi-Trop project): a cohort profile(2016) CARDOSO, Clareci Silva; SABINO, Ester Cerdeira; OLIVEIRA, Claudia Di Lorenzo; OLIVEIRA, Lea Campos de; FERREIRA, Ariela Mota; CUNHA-NETO, Edecio; BIERRENBACH, Ana Luiza; FERREIRA, Joao Eduardo; HAIKAL, Desiree Sant'Ana; REINGOLD, Arthur L.; RIBEIRO, Antonio Luiz P.Purpose We have established a prospective cohort of 1959 patients with chronic Chagas cardiomyopathy to evaluate if a clinical prediction rule based on ECG, brain natriuretic peptide (BNP) levels, and other biomarkers can be useful in clinical practice. This paper outlines the study and baseline characteristics of the participants. Participants The study is being conducted in 21 municipalities of the northern part of Minas Gerais State in Brazil, and includes a follow-up of 2years. The baseline evaluation included collection of sociodemographic information, social determinants of health, health-related behaviours, comorbidities, medicines in use, history of previous treatment for Chagas disease, functional class, quality of life, blood sample collection, and ECG. Patients were mostly female, aged 50-74years, with low family income and educational level, with known Chagas disease for >10years; 46% presented with functional class >II. Previous use of benznidazole was reported by 25.2% and permanent use of pacemaker by 6.2%. Almost half of the patients presented with high blood cholesterol and hypertension, and one-third of them had diabetes mellitus. N-terminal of the prohormone BNP (NT-ProBNP) level was >300pg/mL in 30% of the sample. Findings to date Clinical and laboratory markers predictive of severe and progressive Chagas disease were identified as high NT-ProBNP levels, as well as symptoms of advanced heart failure. These results confirm the important residual morbidity of Chagas disease in the remote areas, thus supporting political decisions that should prioritise in addition to epidemiological surveillance the medical treatment of chronic Chagas cardiomyopathy in the coming years. The SAo Paulo-Minas Gerais Tropical Medicine Research Center (SaMi-Trop) represents a major challenge for focused research in neglected diseases, with knowledge that can be applied in primary healthcare. Future plans We will continue following this patients' cohort to provide relevant information about the development and progression of Chagas disease in remotes areas, with social and economic inequalities. Trial registration number NCT02646943; Pre-results.